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A hormone linked to appetite “could offer hope to prevent Alzheimer’s disease”, according to The Daily Telegraph. The newspaper reported that people with the highest levels of the hormone leptin were four times less likely to develop Alzheimer’s than those with the lowest.

The story is based on research that assessed the levels of leptin, a hormone thought to regulate appetite, in a group of 785 healthy older individuals. These people were then followed for an average of eight years, and any new cases of dementia were documented. The study showed that higher leptin levels at the assessment were associated with a decreased risk of developing Alzheimer’s disease.

This study was relatively small but well conducted, and it encourages further research into the complex associations between leptin, obesity and Alzheimer’s disease. It is too soon to say if leptin can be used as a preventive treatment, but it may have a role in identifying people who are at risk of later developing Alzheimer’s.

Where did the story come from?

This research was carried out by Dr Wolfgang Lieb and colleagues at various US institutions including the Framingham Heart Study research centre in Massachusetts. The study was funded by the National Institutes of Health and The National Heart, Lung and Blood Institute in the US. It was published in the peer-reviewed Journal of the American Medical Association.

The press has generally reported this study well, although some reports have cited research that had looked at obesity as a risk for dementia. This particular study did not look at why different participants had various levels of the diet-related hormone leptin, so the study’s authors did not relate their findings to obesity. The Daily Telegraph reported that the average age of the participants was 72 years, although it was actually 79.

What kind of research was this?

This was a prospective cohort study comparing levels of the hormone leptin and the risk of Alzheimer’s disease. It used data taken from individuals enrolled in the Framingham study, a large cohort study initiated in 1948 to look for risk factors for heart disease within the community. Participants were given assessments every two years in the Framingham study. These included blood tests for levels of leptin, a hormone that is released by fat cells and which signals the brain to modify food consumption over the long term. High levels of leptin are associated with obesity.

The researchers suggest that other studies have shown that leptin can also affect the part of the brain that controls learning and memory. They also suggest that weight loss precedes the onset of Alzheimer’s disease. Given these possible associations they wanted to assess directly whether there was an association between leptin and Alzheimer’s disease.

What did the research involve?

From individuals recruited to the Framingham study from 1990-94 the researchers selected 785 participants with no signs of dementia (average age 79 years). The participants’ first measurements of leptin were taken to be their entry into the study, or ‘baseline’.

The study followed individual participants for a range of 0 to 15.5 years, with an average follow-up time of 8.3 years. Dementia was diagnosed based on a combined neurology and psychology test plus a standard test of cognition called the mini mental state examination. The onset of any dementia was estimated using medical records and structured interviews with family members. A participant was classified as having dementia if they had experienced symptoms for at least six months.

The risk of Alzheimer’s disease is thought to be influenced by numerous factors, including age, gender, level of the amino acid homocysteine and which variant of a gene called ApoE an individual has. As these factors varied in the study population the researchers adjusted their analyses to account for their influence. Other potential factors such as body mass index (BMI), waist to hip ratio, diabetes, smoking and blood pressure treatments were also adjusted for.

Alzheimer’s disease is associated with a decreased brain volume. From 1999-2004 the researchers also measured total brain volumes of 198 participants, on average 7.7 years after baseline.

What were the basic results?

The researchers found that lower leptin levels were associated with a lower risk of developing both Alzheimer’s disease or dementia due to any cause. This remained the case when they adjusted for age, gender, homocysteine, genetic background, waist to hip ratio and vascular risk factors. In this adjusted model, increases in leptin levels were associated with a 32% reduction in the chance of developing dementia due to any cause (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.54 to 0.87). For Alzheimer’s disease alone, increases in leptin reduced the risk by 40% (HR 0.60, 95% CI 0.46 to 0.79).

To compare those with the highest leptin levels to those with the lowest levels the researchers divided the participants into quarters. They found that participants in the lowest quarter had a 25% risk of developing Alzheimer’s after 12 years of follow up, whereas participants in the highest quarter had a 6% risk. They found that when they adjusted for age, gender, homocysteine and genetic background there was a 77% lower risk of developing Alzheimer’s disease for people in the highest leptin quarter when compared to those in the lowest (HR 0.23 95% CI, 0.08 to 0.61). This relationship did not remain significant when they also adjusted for waist to hip ratio and BMI.

The brain measurements showed that participants with lower leptin levels had smaller brain volumes. This remained significant after adjustment for all of the risk factors. The researchers also measured the ventricles. These are normal cavities in the brain that are filled with spinal fluid. Ventricles get larger in Alzheimer’s disease as the brain volume decreases. The researchers initially found that these cavities were increased in participants with lower leptin, but after adjusting for age and gender this was no longer significant.

How did the researchers interpret the results?

The researchers concluded that higher baseline concentrations of leptin were associated with lower incidence (rate of onset) of dementia and Alzheimer’s disease. They said that follow-up work was needed, but if their work was confirmed by others “leptin levels in older adults may serve as one of several possible biomarkers for healthy brain aging”. They also say that “more importantly [this] may open new pathways for possible preventive and therapeutic intervention”.

Conclusion

This study found an association between higher leptin levels and a decreased risk of Alzheimer’s disease. Higher leptin levels were also associated with a lower risk of decreases in brain volume.

This was a very well conducted study, but as it was a cohort study it can only show that leptin is associated with Alzheimer’s disease and cannot show what role leptin plays in the development of, or the protection against, the disease.

Importantly, the researchers note that when adjusting for weight and BMI the association was no longer significant. This means that, as overall weight and BMI are already linked to the development of Alzheimer’s disease, more research will be needed to untangle the role that weight has in relation to leptin levels and Alzhemer’s.

One point to note is that the number of participants was rather small and the researchers endeavoured to adjust for the many risk factors for Alzheimer’s disease. Larger follow-up cohort studies may be beneficial.

Overall, this study shows that further research into the role of leptin in Alzheimer’s is warranted. This research may help to develop new tools that will allow doctors to determine high-risk groups before the onset of Alzheimer’s disease.